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Microbes & Immunity The feature of bladder cancer stem cells

the YAP signaling pathway in BCSCs. Knockdown of YAP interacting with miR-107, thereby promoting the self-
led to decreased expression of stemness genes in BCSCs and renewal of BCSCs. 78
reduced tumorigenicity of BCSCs. Conversely, the exogenous Long non-coding RNA LBCS (low expressed in
addition of YAP enhanced the expression of stemness genes, BCSCs) is downregulated in BCSCs. To explore its
sphere-forming ability, tumorigenicity, and drug resistance potential mechanism in BCSCs, researchers from Sun Yat-
in YAP-low BCSCs. 28 sen University led by Chen Xu have indicated that LBCS
Subsequent investigations revealed that the autocrine directly binds to heterogeneous nuclear ribonucleoprotein
signal PDGF-BB (platelet-derived growth factor-BB) K (hnRNPK) and enhancer of zeste homolog 2 (EZH2),
activated phosphorylation of PDGFR (platelet-derived acting as a scaffold. Through mediating trimethylation
growth factor receptor) in OV6 BCSCs, leading to the of lysine 27 on histone H3, this complex suppressed the
+
activation of downstream kinases ERK (extracellular signal- transcription of SRY-box2 (SOX2). Both in vivo and in
regulated kinase) and MEK (mitogen-activated protein vitro experiments corroborated that LBCS significantly
kinase). Phosphorylated PDGFR bound with cytoplasmic attenuates the self-renewal ability and tumor-initiating
YAP, preventing YAP phosphorylation and promoting YAP capacity of BCSCs. 79
nuclear translocation, thereby maintaining the stemness SOX2, a stemness-related factor, is closely associated
characteristics of BCSCs. In the Hippo pathway, YAP with stem cell characteristics. SOX2 overlapping transcript
forms complexes with TEAD, leading to the upregulation (SOX2OT), a long non-coding RNA, has been identified
of downstream gene transcription levels. Further studies as a potential marker for TSCs. Zhan et al. isolated
have revealed that YAP promotes the expression levels CD44 ALDH1 BCSCs from SW780 and 5637 cells
+
+
of PDGF-BB in OV6 BCSCs through TEAD1, with using flow-activated cytometric sorting. It was confirmed
+
ChIP results indicating TEAD1 binding to the PDGF-BB that both SOX2 and SOX2OT were highly expressed in
promoter, leading to transcriptional activation. The BCSCs, with expression levels approximately 100 times
28
YAP-TEAD1-PDGF-BB-PDGFR pathway also activated higher than those in BCNSCs. Through sphere formation
MEK/ERK kinases and Hippo target genes associated with assays, 5-ethynyl-2’-deoxyuridine (EdU) staining, and
cell carcinogenesis, collectively suggesting that different colony formation experiments, it was revealed that the
pathways mutually maintain the stemness characteristics knockdown of SOX2OT could attenuate the self-renewal
of OV6 BCSCs. capacity of BCSCs. Furthermore, inhibition of SOX2OT
+
slowed down the growth of xenograft tumors and reduced
3.3.6. Non-coding RNA
their metastatic ability in vivo. Mechanically, SOX2OT
Non-coding RNAs play a significant role in the self-renewal primarily localizes in the cytoplasm, acting as a sponge
of BCSCs. Despite approximately 90% of the human for miR-200c. In addition, overexpression of SOX2 could
genome being transcribed, only 2% of the entire genome reverse the inhibition of BCSCs stemness induced by
possesses protein-coding ability. 72,73 Non-coding RNAs, SOX2OT knockdown. 80
which do not encode proteins, serve as crucial regulators Numerous studies have demonstrated the crucial
of gene expression and play essential roles in numerous regulatory role of non-coding RNA in BC. With the
74
74
diseases. Among non-coding RNAs, microRNAs continuous development of genomics, the relationship
(miRNAs), long non-coding RNAs (lncRNAs), and circular between BCSCs and non-coding RNA will be further
RNAs (circRNAs) are prominent. elucidated. This advancement holds the potential to
Circular RNA, acting as a sponge for miRNA, regulates provide more diverse treatment options for BC patients,
the expression of downstream target genes, thereby either enabling more patients to benefit from precision medicine.
promoting or inhibiting tumor progression. 75-77 A research
team led by Song Wu at Shenzhen University conducted 3.4. Drug resistance mechanism
transcriptomic microarray analysis of BCSCs, identifying The medications currently used in clinical treatment
circRNA_103809 as exhibiting the most significant mainly target rapidly proliferating tumor cells, whereas
difference in transcription levels between BCSCs and TSCs typically remain in a quiescent state. Drug
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BCNSCs. Through sphere formation and functional resistance mechanisms in BC include drug efflux
experiments, silencing circRNA_103809 attenuated the and drug conversion into inactive substances, among
sphere-forming ability of BCSCs. Mechanically, pull- others. In addition, the distinct division characteristics
down assays were conducted on miRNA from the human of BCSCs confer resistance to standard chemotherapy,
BC cell line EJ using probes targeting circRNA_103809. allowing for their survival and further differentiation
The results revealed that circ_103809 acted as a sponge and proliferation during chemotherapy intervals. The

Volume 1 Issue 1 (2024) 36 doi: 10.36922/mi.2377